Overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) are diseases with unknown pathology and etiology. OAB and IC/BPS have devastating psychological and social impacts on quality of life, but treatments for these diseases are clinically challenging. Sacral neuromodulation is a FDA approved treatment for OAB. Currently it is only offered to OAB patients after pharmacotherapy has failed. Since its FDA approval for OAB, sacral neuromodulation has been shown to be effective in treating IC/BPS in many clinical trials and is currently listed in the AUA guideline o IC/BPS as one of the suggested treatment options. In addition clinical studies have showed that pudendal neuromodulation is superior to sacral neuromodulation. It successfully treated OAB or IC/BPS patients who have failed sacral neuromodulation. Furthermore, recent multicenter clinical trials have indicated that tibial neuromodulation is effective for treatment of OAB. Although neuromodulation is an effective treatment for OAB or IC/BPS, the mechanism underlying neuromodulation (sacral, pudendal, or tibial) is still unknown. More surprisingly there is very limited effort in basic science research aimed at revealing the mechanism of action underlying neuromdulation. In this project we propose to determine the central sites of action for neuromodulation by answering the following questions: 1. whether neuromodulation acts in the spinal cord or in the brain? 2. Whether it acts on the ascending or descending limbs of the spinobulbospinal micturition reflex pathway activated by bladder A?-fiber afferents or on the spinal micturition reflex pathway activated by noxious C-fiber bladder afferents? 3. What neurotransmitters are involved in neuromodulation? 4. How brain sensory and motor activity associated with bladder nociception/overactivity is altered by neuromodulation? Different neuromodulation methods (sacral, pudendal, or tibial) will be investigated and compared to answer these questions. Identifying the sites of action for different neuromodulation therapies will surely guide clinicians and patients in selection of the optimal treatment strategies and thereby significantly improve the clinical outcomes in treating OAB or IC/BPS. Information about the sites of action and the neurotransmitter mechanisms underlying neuromodulation could also be useful in developing new drugs to treat OAB or IC/BPS. Our studies will significantly benefit millions of Americans suffering from OAB or IC/BPS.